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Patented Feb. 13, 1940 UNITED? STATES PATENT OFFICE 2,190,444 i I v 'DERIVATIVES OF 2.6 qummnoxvrsmh DINE-4-C'ARBOXYLIC ACID AND A OD OF MAKING THE SAME METH- Max Dohrn, Berlin-charlottenburg, and Hans Nahme, Berlin-Zehlendorf, Germany N Drawing. Application March 19, 1937, Serial 'No. 131,784. In Germany March 23, 1936 13 Claims. (01. zen-e95 Y This invention relates to derivatives of 2.6-

dihydroxypyridine-4-carboxylic acid and a method ofmaking the same.

In accordance with the present invention comformula:

pounds of the general ooox or the tautomeric form ooox N/OX' H in which X indicates substituted ornon-substituted hydrocarbon residues; such as alkyl,

, phoacetic acid, methionic acid-benzene or toluene sulphonic acids, naphthalene sulphonic acid or the like. The ether-esters thus formed are very easily-soluble inmost organic solvents and due .to thisproperty can be separated by known processes from small quantities of unchanged starting. material and the simultaneously-formed, nonetherified esters. The free ether-acids. are obtained in a simple manner by saponification of these ether-esters. It is stated in the literature in Beilsteins Handbook of Organic Chemistry, vol. 22, 4thedition (1935), page 257, that on treating citrazinic acid with methanol in the presence of a specific condensing agent, namely hydrochloric acid, 2.G-dihydroxypyridine--carboxylic acid methyl ester is formed. However, it is not possible to simultaneously succeed in etheri fying one hydroxyl group by means of this agent. Hence, in contrast to theknown behavior of hydrochloric acid the claimed condensing agents havea very specific and new effect upon the present starting materials due to their etherifying action.

' added about acm M. P. 205 0..

, Z-hydroxy-6-cyclohexyloxy-pyridine-4-carboxylic acid cyclohexyl ester, afterrecrystallisation from The mono-ethers carboxylic' acids and their of 2.6-dihydroxy-pyridine-i- I esters obtained according to the present process constitute a class ofnew pyridine derivatives which find applica;

tion as intermediate products for the manufac- ,tureof pharmaceutical preparations. Such preparations containing in the molecule pyridine or quinoline carboxylic acid compounds are known. For instance, analogous products are described v in applicants Patents Nos. 2,138,628and 2,06 l ,-"1 297. v

The following examples illustrate the invention the parts being by weight:

' Example 1 v v To 100 parts of butyl alcoholah'd-15L5 parts of 2.6 dihydroxy pyridine 4 carboxylic acid are parts of thionyl chloride. This water bath until mixture is then. heated on the v the acid is completely dissolved. The thionyl zo chloride and the excess butyl alcohol are thereupon distilled'off and the residue extracted by shaking with sodium carbonate solution and ether. The ether solution contains the 2-hydroxy-6-butoxy-pyridine-4-carboxyhc acid butyl gg ester, which after distilling off the ether and recrystallising from petrol-ether melts at 60 to 61 C. On saponification is produced the free 7 Example 2 g r 2331 parts of 2.6-dihydro7ky-byridine-4carboxylic acid cyclohexyl ester or M. P. 218 C. are

boiled in 75 parts of cyclohexanol with 10 parts of concentrated sulphuric acid for about 1 hour 833 under a reflux condenser, whereupon with a descending condenser a portion of the reaction mixture, consisting of 'cyclohexanol and water is distilled off. The contents of the flask after cooling are washed several times with water and the ex- 52 cess of alcohol distilled ofi with steam; As in "Example 1 the ether-ester is then'separated with sodium carbonate and ether. The ether soluble petrol-ether melts at 97 C. and the free acid 1 obtained therefrom by saponification at 223 C.

Example 3 sage of a current of indifierent gas, for example, carbon dioxide or nitrogen in such a manner that at a very slow rate a mixture of isoamyl alcohol and water distils off, then practically the whole of the acid is converted into the 2-hydroxy 6 isoamyloxy-pyridine-4-carboxylic acid l isoamyl ester which is isolated from the reaction mixture, for example, in the manner set forth in Example 2. M. P. 82 C. The corresponding free acid melts at 258 C. with decomposition.v

In the same manner Z-hydroxy-G-ethoxy-pyrim dinel-carboxylic acid ethyl ester is which exhibits the melting point 67 C.

Of course, many changes and variations in the reaction conditions and the like may be made by those skilled in the art in accordance with the 15 principles set forth herein and in the claims annexed hereto.

What we claim is:

1. Process for the manufacture of mono-ethers of 2.6-dihydroxy-pyridine--carboxylic acid comzopounds, comprising reacting a 2.6-dihydroxypyridine--icar boxylic compound with a compound containing an alcoholic group which is the residue of a monobasic alcohol taken from the class consisting of saturated aliphatic alcohols $25 and cyclic alcohols saturated in the alcohol radical in the presence of an etherifying agent.

2. Method according to claim 1 wherein the etherifying agent'is selected from the group of compounds consisting of thionyl chloride, sul- 'f30 phuric acid, perchloric acid, phosphoric acid,and

organic sulphonic acids. i

3. Method according to vclaim 1 wherein a' 2.6- dihydroXy-pyridine-4-carboxylic acid ester is used as starting material.

4. Method according to claim 1 wherein 2.6- dihydroxy-pyridine-l-carboxylic acid is used as starting material.

5. A method forithe manufacture of monoethers of 2.6-dihydroxy-pyridine-4carboxylic .50 cohol taken from the class consisting of saturated aliphatic alcohols and cyclic alcohols saturated inthe alcohol radical.

7.. A mono-ether of 2.6-dihydroxy-pyridina-4- carboxylic acid of the structural formula wherein X represents a hydrocarbon radical which is the residue of a monobasic alcohol taken produced I phatic alcohols and acid wherein 2.6-dihydroxy-pyridine-4-carboxyle 7 from the class consisting of saturated aliphatic alcohols and cyclic alcohols saturated in the al I cohol radical.

8. A mono-ether of a 2.6-dihydroxy-pyridinel-carboxylic acid ester of the following structural formula I .oooY

HO LN OX wherein X and Y represent hydrocarbon radicals which is the residue of a monobasic alcohol taken from the class consisting of saturated alicyclic alcohols saturated in the alcohol radical.

9. -hydroxy-6 hutoxy+pyridine-4- carboxylic acid 'butyl ester having the melting point '60-61" C. and yielding, on saponification, an acid of the melting point 252 C.

1i). z-hydroxy fi-cyclohexyl-oxypyridinee l-car- 4 boxylic acid cyclohexyl ester having the melting point 97 C. and yielding, on saponification, an acid of the melting point 223 C. p f v I 1 1. 2-hydroXy-6-isoamyl oxypyridine 4 carpoint of 82 C. and yielding, on saponification, an

sition). v

12.,A mono-ether of ,2.6-dihydroxy-pyridinel-carboxylic acid of the structural formula; j

roa 3 'wh'erein X represents a hydrocarbon radical which is the residue'of a monobasic alcohol taken from the class consisting ofisaturated aliphatic alcohols andcyclic alcohols saturated in the alcoholradical. I g

1 A mono-ether of 2.6-dihydroxy-pyridine- 4-carboxylic acid ester of the structural formula wherein X and Y each represents a hydrocarbon radical which isthe residue of a monobasic alcohol taken from the class consisting of saturated aliphatic alcohols and cyclic alcohols saturated tor acid isoamyl ester having the melting 

